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san1
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Deuterated drugs derived from fungi? Questions and thoughts.
#26946575 - 09/20/20 05:23 PM (3 years, 4 months ago) |
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Deuterium is an isotope of hydrogen, also called 2H. A stable and heavy isotope of hydrogen, it's chemical interactions are roughly similar to that of the much more abundant 1H, with slight differences in the length of the electron bonds it's connected to. The increased mass also creates a lower reaction rate of molecules derived from it due to the kinetic isotope effect.
When replacing hydrogen with deuterium in pharmaceutical applications the result is a generally longer biological half life, meaning the drugs stay in the system longer.
Deuterium occurs at a rate of one in every 6420 hydrogen atoms in the ocean, and is concentrated in industrial processes through chemical reactions, distillation and/or electrolysis.
When first looking into this I expected D2O to be metabolically inert or nearly so, assuming the precursors for drugs produced by fungi to mainly come from plants. While this is generally true, there are a few steps in which fungi may directly draw from it's own available water sources to synthesize metabolites. In the following paper scientists were able to produce deuterated penicillin by growing penicillium directly in the presence of D2O:
Carlstedt, B. C., Crespi, H. L., Blake, M. I., & Katz, J. J. (1970). Biosynthesis of Deuterated Benzylpenicillins I: Solvent Deuterium Oxide Participation. Journal of Pharmaceutical Sciences
Some questions I'm interested in:
What role does water play in the actual metabolic processes of fungi, as opposed to it's simple function as a solvent and medium? Can D2O be successfully substituted?
What changes would deuteration have on the effects of drugs derived from fungi? Could the lower reactivity result in less frequent dosages for chronic long term treatments? Would the decreased reactivity necessarily reduce the efficacy of anti-fungals and antibiotics?
Edited by san1 (09/20/20 05:29 PM)
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Solipsis
m̶a̶d̶ disappointed scientist


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Re: Deuterated drugs derived from fungi? Questions and thoughts. [Re: san1]
#26948035 - 09/21/20 03:47 PM (3 years, 4 months ago) |
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As H2O contains a bunch of OH- and H3O+ as dissociation products (rapidly dissociating and recombining) and i guess some protons, the same would be true for deuterium. So the moment you have some acid or alcohol present (i mean as a chemical group or function, even of a bigger biochemical), its protons will also dissociate back and forth in an equilibrium of being attached and swimming around in a soupy balance.
You can see where this is going.. D+ and H+ could switch places essentially, as metabolites do their thing so soon enough it should be everywhere. I don't know at what point enzymes may secure D more in place on a molecule like a C-D bond rather than an O-D bond. But it doesn't even matter for penicillin as it has an acid function where the deuterium could go just by swapping and eventually getting isolated as pure solid dry compound. So its not even really a reaction, its just substitution by dissociation.
Maybe on psilocin it could be a good place for deuterium to go on the indole N, also on the indolol oxygen but that is more liable to get phosphorylated and dephosphorylated. But either way.
And yes iirc it does make a difference with D in drugs - for one, it can make enzymes not fit well, better, differently.. but the difference may be small, just a little bit different bond length. But generally there may be difference in metabolism of the drug, other pharmacokinetics.
Correct me anyone if i am totally off the mark here.
Edited by Solipsis (09/21/20 03:54 PM)
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san1
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Re: Deuterated drugs derived from fungi? Questions and thoughts. [Re: Solipsis]
#26950133 - 09/22/20 09:15 PM (3 years, 4 months ago) |
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Quote:
Solipsis said: As H2O contains a bunch of OH- and H3O+ as dissociation products (rapidly dissociating and recombining) and i guess some protons, the same would be true for deuterium. So the moment you have some acid or alcohol present (i mean as a chemical group or function, even of a bigger biochemical), its protons will also dissociate back and forth in an equilibrium of being attached and swimming around in a soupy balance.
Correct me anyone if i am totally off the mark here.
That's true for ionic solutions, but complex molecules like amino acids don't dissociate in water. Any protium in fungi feedstock would be retained lock-step through the same pathways whether the fungus is given D20 or H20.
I think there are other mechanisms where D can bump around like that, but mostly it's pretty deterministic. The paper I linked to talks about how certain deuterium substitutions happen at predictable positions in the final product.
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Solipsis
m̶a̶d̶ disappointed scientist


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Re: Deuterated drugs derived from fungi? Questions and thoughts. [Re: san1]
#26957487 - 09/27/20 01:46 PM (3 years, 3 months ago) |
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I think that is incorrect.
Weak acids and alcohols dissociate slightly in aqueous environment despite the O-H (/ O-D) being a covalent bond. Like methanol and ethanol do. Physiological environments are ionic solutions but I guess you meant strictly inorganic salts with ionic bonds.
I believe thats far too much of a black and white view of the difference in bonds and dissociation (and 'bumpings around').
Amino acids are not complex molecules just organic. Do you mean proteins, which are made up of a folded jumble of a linked chain of amino acids?
Regardless, tyrosine, serine and threonine have a hydroxy function...
As I already said, I don't think you are likely to suddenly find a D linked to a carbon in your final product, but another mechanism rather than the dissociation seems to just consider (in a way the inverse) how protons are Lewis acids and may just protonate say the indole amine N of psilocin or psilocybin.
So whats to stop a deuteron (or D3O+ or whatever complicated ratio of partial deuteration) from doing that to psilocin or psilocybin "on occasion" and bumping off a proton? Seems like it does not really matter if it is rare because it would be similarly rare to dissociate off again whatever the rate, giving you an equilibrium.
Predictability, favorable positions would just seem to be related to which positions are amenable from a set of factors.
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